Archive for the ‘Aging’ Category

Professor Cynthia Kenyon is a pioneering researcher in the biology of aging. A couple years ago, she presented a Harvey Lecture at Rockefeller University on her work; that lecture was similar to the one I heard her give at last year’s Woods Hole summer school course on aging. I think that it’s worth highlighting some of the things she has to say.

“We began our studies in the early 1990s. At that time, and for years before, many people assumed that aging was a haphazard process, not subject to regulation. Our tissues just break down, and we die. But the more I thought about it, the more I started to question this view. A mouse lives two years, whereas a bat can live 30 years or more. A rat lives three years; a squirrel, 25. These animals differ by their genes, so there must be genes that affect aging. Also, nothing in biology seems to “just happen”; everything seems to be regulated, often in quite an extraordinary way.

My experience as a developmental biologist sharpened my thoughts about aging. People were once very skeptical about looking for developmental genes. Treating frog embryos with acid can produce a second head, and inhibiting pyrimidine synthesis in flies produces small wings, so many people thought that genes affecting development would also affect things like the Krebs cycle, or pH. They were wrong. There is a dedicated regulatory circuitry for pattern formation. In addition, many people thought that developmental mechanisms would differ completely in different kinds of animals, but again they were wrong. In fact, the degree of evolutionary conservation is striking. So it seemed to me that something as fundamental as aging might also be subject to regulation. Maybe there would be a molecular longevity “dial,” like a thermostat, that is universal but set to run at different rates in different kinds of animals. The dial would be turned up in mice (which age quickly) and down in bats (which age slowly). I wrote extensively about this in the 1990’s (Kenyon, 1996, 1997), suggesting, for example, that aging might be regulated by something like the heterochronic genes of C. elegans, which control the timing of developmental events.”

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“Since we obtained such a long lifespan when we killed the gonads of daf-2 mutants, we wondered what would happen if we reduced daf-2 activity even more in these animals. Using a stronger daf-2 allele would run the risk of triggering dauer formation, but we found that we could dodge dauer formation if we subjected long-lived daf-2(e1368) mutants to daf-2 RNAi soon after hatching. When we did this, and killed the gonads as well, the animals lived six times as long as normal (Fig. 2.16). Incredibly, the animals remained healthy and vigorous for a very long time. In fact, when Nuno Arantes-Oliveira, the graduate student doing this work, showed two 144-day-old animals, still moving around, to other lab members and asked them to guess the age of the animals, they reckoned five days! [For a movie of these two spunky animals, see Arantes-Oliveira et al. (2003).] It is remarkable that with just a few minor changes, it is possible to produce such an enormous lifespan extension (the equivalent of 500 years in humans) with no obvious effect on the vitality of the animals.”

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“If we really could live longer, remaining youthful and disease-free, why haven’t scientists been working on this already? First, as I said, they didn’t think it was possible, since aging was thought to be unruly and random. Second, and even more important, we haven’t had any role models to emulate, primates that shoot rockets to the moon, go to the opera, and live for 300 years. If we did, we might already know how to stay young and live much longer than we do. We invented airplanes because we could see birds could fly. Now that we know that animals can live longer than they do, perhaps soon we will learn how to extend our own youthfulness and lifespan. It may not be that difficult. Since there are short-lived and long-lived insects, birds, and mammals, longevity must have evolved not just once but many times. Maybe the path to increased longevity is in us already, in the form of a network of genes and proteins, waiting to be nudged in just the right way.”

I recommend you read the whole thing–it’s quite readable, and the scientific results are breathtaking.

And if you’re interested, here is a video from earlier this year with Charlie Rose interviewing a panel of biologists about the remarkable progress that has been made in aging research recently. Members of the panel include Kenyon and Lenny Guarente, another leader in the field whose book I previously reviewed.

As I mentioned in a previous post, I was lucky to be able to attend, as a student, the 2006 Molecular Biology of Aging summer course at the Woods Hole Marine Biology Laboratory. This three week course was intensive; part the time was spent in lectures, where many of the world’s leading experts on aging explained their research in detail (and the students were able to ask lots of questions), and the rest was spent in the lab. There was also often time to attend some of the many other stimulating talks in molecular biology or neuroscience being held elsewhere at Woods Hole. Because the subject was so far from my normal research, I took vacation time to attend; I suppose it doesn’t seem like much of a vacation, but in fact Woods Hole is incredibly stimulating, and it was one of the most memorable and refreshing vacations I’ve ever had.

The RNAi technique lets you suppress the transcription of any single gene in the worm’s genome. An “RNAi screen” means that you divide the population of worms that into groups organized so that each group has a different gene suppressed, and you make sure that you have a group for each gene in the genome. For each group of worms, you check whether it has some phenotype that you’re interested in (in our case it was the ability to breed at a later age than usual). That way, you can quickly find genes that are involved in the phenotype.

The picture above is from the lab at Woods Hole. From left to right are Michael Morissette, Andrew Midzak, Serkalem Tadesse, myself, and John Cumbers. The others have finished their work, but I was slower than everybody else, so I’m guessing that I was still counting worms or something.

Biologists work incredibly long hours at the lab, often doing work that is exciting in terms of its implications, but sometimes pretty dull and repetitive in the doing; biologists are dedicated people! On the other hand, lab life seems much more social compared to the life of a computer scientist or physicist. (Although there is much more social interaction in those fields than in fields like history, as I know by observing my historian wife. I always find it ironic that humanists, who tend to be outgoing people, usually find themselves working in a much more solitary way than scientists.)

One thing I learned was that lab biology is largely a matter of learning and using “protocols,” which are basically like scientific recipes. Take a look at this amusing video, which features the highly talented John Cumbers (who was one of my lab-mates) and produced by the Brown iGEM team:

Another protocol was for “picking” worms (moving them from one petri dish to another). An adult C. Elegans is only about 1 millimeter long, so picking them up is not easy. You do it under a microscope with a special thin wire (a “picker”). You sort of try to scoop them up, but the worms run away! It’s like a video game, except not nearly as fun, really. Here’s a video showing the technique in action.

You should notice by the way that the picked worm is glowing. That’s because the worm is a mutant: a gene for a fluorescent protein has been spliced into its genome attached to another gene (daf-12) of interest. That way you can know where daf-12 is expressed in its body. (This video was submitted by user a99xel to YouTube).

Although we now are capable of manipulating the aging process, including significantly extending the lifespan of many laboratory animals, it is still a frustrating fact that there is no consensus about the ultimate cause or causes of aging.

One viewpoint, which is probably only held by a significant minority of scientists in the field, is that the aging process is strongly connected to mitochondria, which are the power plants or batteries of our cell, converting nutrients into useful packets of energy in the form of ATP. We’re used to the idea that electronic equipment fails when the batteries go dead, so it’s not such a stretch to take a close look at the mitochondria.

What’s more, mitochondria produce much of the “pollution” in the cell in the form of the free radicals that are a by-product of the oxidative phosphorylation process (the process that turns nutrients into energy). Those free-radicals can damage proteins or DNA, particularly the mitochondrial DNA (this is special DNA, inherited from the mother, that resides in the mitochondria rather than the nucleus) that codes for a few essential mitochondrial proteins.

So one theory says that there is a kind of vicious circle, whereby old mitochondria start emitting more free radicals, which further damages the mitochondria, until the mitochondria are so damaged that they don’t produce sufficient energy and start damaging the rest of the cell. Right now, the consensus view on whether the experimental facts really fit that theory is “Maybe.”

If you want to learn more about mitochondria, I highly recommend “Power, Sex, Suicide: Mitochondria and the Meaning of Life (you’ve just got to love that title), by Nick Lane. Lane’s book is popular science, but it’s a very deep book, and actually proposes theories, including theories of aging, that you won’t see elsewhere in the literature. It’s not an easy book to read, but it’s very worthwhile.

Alternatively, you might enjoy this video of Douglas Wallace lecturing on the role of mitochondria in diseases and aging. Wallace, a professor from UC Irvine, delivers highly entertaining and persuasive lectures.

MIT professor Lenny Guarente is a pioneer and leader in the study of the molecular biology of aging. This book is a popularized account of some of the early research that he and his students and post-docs conducted; research that helped move the study of aging from being a kind of slightly disreputable scientific backwater to one of the most dynamic and exciting fields of modern molecular biology. Guarente’s research focused on sirtuins, which are proteins that are now understood to retard aging in a wide variety of organisms, with mechanisms that vary depending on the organism.”

Ageless Quest” is an easy read and a great introduction to the field. It had a surprising amount of impact on me; after reading this book I decided that I wanted to learn more about what was happening in this very important field, so I audited an MIT reading course on the molecular biology of aging taught by Angeiszka Czopik and Danica Chen, two post-docs in Prof. Guarente’s lab, and then I attended the 2006 Summer School Course on the molecular biology of aging at Woods Hole’s famous Marine Biological Laboratory, organized by Gary Ruvkun and Steve Austad.

This book probably won’t have that big an impact on you! It’s a pretty light book weighing in at only 154 pages; but you can learn a lot whether or not you have a background in biology.